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Emil Kraepelin, the founder of modern psychiatric classification, and the Nobel laureate Julius Wagner von Jauregg highlighted the role of infections and the immune system in psychiatric disorders. It is well known that infections can trigger various psychiatric syndromes and influence the course of psychiatric disorders. Psychiatric symptoms during virulent infections, often presenting as encephalitis or meningitis, normally are diagnosed as mental disorders due to a general medical condition. On the other hand, an expanding research field underpins the view that infections and activation of the immune system may play a causative role in major psychiatric disorders such as schizophrenia or major depression. Also in other psychiatric syndromes, such as Tourette's syndrome, inflammation - partially based on infections - is involved. For this mild smoldering inflammatory process, the ‘mild (chronic) encephalitis' concept was developed. In this chapter, findings related to immune activation and inflammation in schizophrenia, major depression and Tourette's syndromes as examples for this concept are described. Moreover, encouraging results from randomized clinical trials in schizophrenia and major depression showing a benefit of anti-inflammatory therapy in these psychiatric disorders are discussed as examples for immunomodulating treatment approaches in psychiatric disorders. Further immunotherapies used in Tourette's syndrome or pediatric autoimmune disorders associated with streptococci are highlighted as further examples for such a therapeutic approach.

Humans are constantly being assaulted by infectious agents. Fortunately, we have evolved a complex process, the immune response, to help fight and clear infection [1]. The immune response evoked by an infectious agent may or may not generate clinical symptoms, depending on the exact type and degree of response. Infectious diseases are well known to provoke psychiatric symptoms. As early as 1890, Emil Kraepelin, one of the founders of modern psychiatry, described during an influenza epidemic 11 cases of psychiatric disorders that presented with different symptoms such as depressed mood, a paranoid and hallucinatory syndrome, involuntary movements, cognitive deterioration, and a delirious state [2]. Later, Kraepelin postulated in his programmatic essay ‘Objectives and methods of psychiatric research' to make the immunological defense and adaption system a focus of psychiatric research [3,4]. There are also numerous descriptions of an association between chronic inflammation of the central nervous system (CNS) and psychopathological states [5]. For example, symptoms of depression and schizophrenia have been described in a certain form of multiple sclerosis [6]. The same is true for viral CNS infection with herpes simplex virus types 1 [7] and 2 [8,9] and measles [10]. Autoimmune processes, such as poststreptococcal disorders, lupus erythematodes and scleroderma, may present primarily as a psychopathological syndrome [11,12,13,14,15,16,17,18]. This line of evidence led to the concept of ‘mild encephalitis' [19].

In modern diagnostics, psychiatric symptoms coexisting with severe infections are diagnosed as ‘mental disorders due to a general medical condition'. Infections can cause a broad spectrum of psychiatric symptoms, e.g. delirium, psychotic disorder or mood disorder (table 1) [20].

Table 1

Diagnostic criteria DSM-IV: psychopathological states due to a general medical condition

Diagnostic criteria DSM-IV: psychopathological states due to a general medical condition
Diagnostic criteria DSM-IV: psychopathological states due to a general medical condition

Factors influencing the psychiatric presentation of infections are the subject of intense research and might include the pathogen, individual medical history and locus of infection. Infections of the CNS, such as meningitis and encephalitis, are believed to be more commonly associated with psychiatric symptoms than those of the peripheral organs, although peripheral infections are also well known to cause psychiatric disturbances. An example is ‘sickness behavior' as a model for depressive disorder, as described below.

‘Sickness behavior', the reaction of an organism to infection and inflammation, is well established as a model for depression in animals and humans [21,22]. The model is based on the observation that increased levels of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), are associated with depressive-like behavior in animals, including decreased drive and motivation, lack of energy and appetite, tiredness, and weight loss. The involvement of cytokines in the regulation of sickness behavior in humans has been studied by administering the bacterial endotoxin lipopolysaccharide to healthy volunteers [23]. Levels of anxiety, depression and cognitive impairment were found to be related to the levels of circulating cytokines [23,24].

The findings of these studies, together with the sickness behavior model, have led to the hypothesis that ‘cytokines sing the blues', i.e. cytokines and a proinflammatory immune state are involved in the pathogenesis of major depression [25,26]. This view is supported by recent literature showing signs of a proinflammatory immune state in major depression.

The innate immune system, which includes natural killer cells and monocytes, for example, as the first barrier against infection, is phylogenetically the oldest part of the immune system. The adaptive immune response with the antibody-producing B lymphocytes and the T lymphocytes (helper T cells) is the pathogen- and antigen-specific component of the immune system. Cytokines regulate all cellular components of the immune system and are involved in both the innate and the adaptive immune response. Helper T cells are of two types: T helper 1 (Th-1) and 2 (Th-2). Th-1 cells produce the characteristic ‘type 1' activating cytokines such as IL-2 and interferon-γ. However, since not only Th-1 cells, but also certain monocytes/macrophages (M1) and other cell types, produce these cytokines, this type of immune response is called the type 1 immune response. The humoral, antibody-producing arm of the adaptive immune system is mainly activated by the type 2 immune response. Th-2 and certain monocytes/macrophages (M2) produce mainly IL-4, IL-10 and IL-13 [27]. Another terminology system differentiates cytokines as being proinflammatory and anti-inflammatory. Proinflammatory cytokines such as TNF-α and IL-6 are primarily secreted from monocytes and macrophages, and activate other cellular components of the inflammatory response. While TNF-α mainly activates the type 1 response, IL-6 activates the type 2 response, including antibody production. Anti-inflammatory cytokines such as IL-4 and IL-10 help to downregulate the inflammatory immune response (table 2).

Table 2

Components of the innate and adaptive immune system

Components of the innate and adaptive immune system
Components of the innate and adaptive immune system

Elevated plasma concentrations of C-reactive protein (CRP) are a common marker of an inflammatory process. CRP levels have been repeatedly observed to be higher in people with depression than in healthy controls, for example in severely depressed in-patients [28], and high CRP levels have been found to be associated with the severity of depression [29]. Higher CRP levels have also been found in both men [30,31] and women [32,33] in remission after a depressive state. In a sample of older healthy persons, CRP levels and IL-6 levels were predictive of cognitive symptoms of depression 12 years later [34]. In comparison to acute inflammatory diseases, such as pneumonia, however, the CRP increase is slight.

Characteristics of immune activation in major depression include increased numbers of circulating lymphocytes and phagocytic cells, upregulated serum levels of markers of immune activation, higher serum concentrations of positive acute phase proteins coupled with reduced levels of negative acute phase proteins, and increased release of proinflammatory cytokines such as IL-1β, IL-2, TNF-α and IL-6 (through activated macrophages) and interferon-γ (through activated T cells) [35,36,37,38,39,40,41]. Interferon-α is well documented to induce severe depressive symptoms, including suicidality, in about one third of patients [42]. Different research groups [43,44,45] have described increased numbers of peripheral mononuclear cells in major depression, and, in accordance with findings of increased monocytes and macrophages, an increased level of neopterin, a marker for activated macrophages, has also been described [46,47,48,49]. The role of cellular immunity, cytokines, and the innate and adaptive immune systems in depression has been recently reviewed [50,51]. Table 3 summarizes several examples for immune markers in major depression.

Table 3

Examples for immune markers reflecting immune activation in major depression

Examples for immune markers reflecting immune activation in major depression
Examples for immune markers reflecting immune activation in major depression

Although immune activation is well established in major depression and infections are well known to trigger depressive symptoms, the association between infection and major depression has not been properly studied. In contrast, the etiology of immune activation in major depression is the subject of intense research.

The results of a prospective population-based Danish register study in 3.6 million people born between 1945 and 1996 support the view that an infection or autoimmune disease significantly increases the risk of a depressive disorder. Participants were followed up from 1977 to 2010, for a total of 78 million person-years. All people diagnosed with an affective disorder according to ICD-8, ICD-9 or ICD-10 and at least one in- or outpatient hospital contact due to an affective disorder (including bipolar disorder) were included. Every previous hospital contact due to an autoimmune disorder or infection (apart from HIV/AIDS) was then recorded. Over 91,000 cases of affective disorder were identified, of which approximately 30,000 had previously been diagnosed with infection and >4,000 with an autoimmune disease. The results show that hospitalization for infection significantly increased the risk for later mood disorder by 63% [incidence rate ratio (IRR) 1.63 (95% CI: 1.61-1.66)] and hospitalization for autoimmune disease significantly increased it by 45% [IRR 1.45 (95% CI: 1.39-1.52)]. Both risk factors interacted and increased the risk to an IRR of 2.35 (95% CI: 2.25-2.46). The findings do not support the hypothesis that primarily CNS infections result in later symptoms of mood disorders as, for example, the risks were higher for hepatitis infection [IRR 2.82 (95% CI: 2.58-3.08)] than for sepsis or CNS infections. Interestingly, the risk for mood disorder increased with the proximity of time to the infection, with the highest risk within the first year [IRR 2.70 (95% CI: 2.60-2.80)] [52]. Since only infections and autoimmune disorders resulting in a hospital contact were recorded, the risk for a mood disorder might be higher when all infections are considered.

There are numerous descriptions of an association between (chronic) inflammation of the CNS and schizophrenia [5]. For example, symptoms of schizophrenia have been described in the encephalitic form of multiple sclerosis [6], in viral CNS infection with herpes simplex virus types 1 [7] and 2 [8], and measles [10], and also in autoimmune processes such as poststreptococcal disorders [11,12,13,14], lupus erythematodes and scleroderma [15,16,17,18]. Schizophreniform symptoms in primary infectious diseases are diagnosed according to DSM-IV as a mental disorder due to a general medical condition (whereas in earlier times the diagnosis was ‘organic brain disorder'). However, we do not know whether schizophreniform symptoms are ‘secondary' to an infection or autoimmune process or the infection is a comorbid condition in a person with a ‘primary' diagnosis of schizophrenia.

Signs of inflammatory degradation products have been described in schizophrenic brain tissue [53] and in the cerebrospinal fluid of about 50% of people with schizophrenia [54]. Furthermore, a blunted type 1 and (compensatory) increased type 2 cytokine pattern have been repeatedly observed in people with unmedicated schizophrenia [55]. Recently published reviews on the imbalance of types 1 and 2 and pro- and anti-inflammatory immune systems as well as innate immunity, including the monocytic system, in schizophrenia have indicated that an inflammatory process plays an important role in the pathophysiology of (at least) a subgroup of people with schizophrenia [56,57].

Over the last five decades, research on the neurobiology of schizophrenia has focused overwhelmingly on disturbances of dopaminergic neurotransmission [58]. A disturbance of the dopamine system is clearly involved in the pathogenesis of schizophrenia, although the mechanism is unclear and antipsychotic antidopaminergic drugs still show unsatisfactory therapeutic effects.

IL-1β, which can induce the conversion of rat mesencephalic progenitor cells into a dopaminergic phenotype [59,60,61], and IL-6, which is highly effective in decreasing the survival of fetal brain serotonergic neurons [62], seem to have an important effect on the development of the neurotransmitter systems specifically involved in schizophrenia, although the specificity of these cytokines is a matter of discussion. Maternal immune stimulation during pregnancy increased the number of mesencephalic dopaminergic neurons in the fetal brain, and the increase was probably associated with a dopaminergic excess in the midbrain [63]. Persistent pathogens might be key factors that drive imbalances of the immune reaction [18]. Nevertheless, many questions remain unanswered about how immunity and immune pathology in virus infections interact in order to show clinical symptoms [64].

Much evidence indicates that a lack of glutamatergic neurotransmission, mediated via NMDA antagonism, is a key mechanism in the pathophysiology of schizophrenia [65]. Kynurenic acid, the only NMDA receptor antagonist known to occur naturally in the human CNS [66], is one of at least three neuroactive intermediate products of the kynurenine pathway. In schizophrenia, a predominant type 2 immune response inhibits the enzyme indoleamine 2,3-dioxygenase, resulting in an increased production of kynurenic acid and consequently in NMDA receptor antagonism [65,67]. The recent finding of NMDA receptor antibodies in about 10% of patients with acute and unmedicated schizophrenia is especially interesting in this regard (fig. 1).

Fig. 1

The enzyme indoleamine 2,3-dioxygenase (IDO) is activated by proinflammatory cytokines [and prostaglandin E2 (PGE2)] and inhibited by anti-inflammatory cytokines. IDO degrades kynurenine, serotonin and melatonin, and influences the concentrations of these neuroactive metabolites and neurotransmitters. The enzyme KMO [kynurenine 3-monooxygenase (identical with kynurenine 3-hydroxylase)] drives the metabolism to the neurotoxic metabolite quinolinic acid. The enzyme KAT (kynurenine aminotransferase) drives the metabolism to kynurenic acid.

Fig. 1

The enzyme indoleamine 2,3-dioxygenase (IDO) is activated by proinflammatory cytokines [and prostaglandin E2 (PGE2)] and inhibited by anti-inflammatory cytokines. IDO degrades kynurenine, serotonin and melatonin, and influences the concentrations of these neuroactive metabolites and neurotransmitters. The enzyme KMO [kynurenine 3-monooxygenase (identical with kynurenine 3-hydroxylase)] drives the metabolism to the neurotoxic metabolite quinolinic acid. The enzyme KAT (kynurenine aminotransferase) drives the metabolism to kynurenic acid.

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Findings regarding kynurenic acid in schizophrenia vary. Elevated kynurenic acid has mainly been described in the cerebrospinal fluid [68,69,70] and in the brains of people with schizophrenia [71,72], as well as in animal models of schizophrenia [73]. However, no increased kynurenic acid levels have been described in the peripheral blood of people with first-episode schizophrenia [74] or in other groups of people with schizophrenia [75]. Increased neopterin values are to be mentioned here again [76]. Antipsychotic medication, however, affects kynurenine metabolites and has to be regarded as an interfering variable [74,75,77].

The proposed involvement of immune activation and inflammation in the pathogenesis of schizophrenia has led to the hypothesis that infectious agents may be involved. Many recent studies have focused on members of the virus family of Herpesviridae [78], Borna virus [79], intracellular bacteria like Chlamydia[80] and the protozoan organism Toxoplasma gondii[81]. The roles of Cytomegalovirus and T. gondii have been stressed for many years [82]. These agents are the focus of research because of their ability to establish persistent infections within the CNS and the occurrence of neurological and psychiatric symptoms in some individuals infected with these agents [83].

The group of Danish researchers mentioned above performed a study in schizophrenia similar to their study in affective disorders [127]. They found that severe infections and autoimmune disorders also additively increased the risk of schizophrenia and schizophrenia spectrum disorders. However, this large-scale study did not confirm infections in the parents, including intrauterine infections, as definite risk factors. Despite its large scale, the study's sensitivity was not very high because only infections associated with a contact to a Danish hospital were recorded, meaning that the risk factors which were identified may only have been the ‘tip of the iceberg'.

Animal models of schizophrenia show that stimulation of the maternal immune system by viral agents leads to typical symptoms in the offspring. Evidence for pre- or perinatal exposure to infections as a risk factor for schizophrenia has been obtained not only from animal models, but also from studies with various viruses in humans. Increased risk for schizophrenia in the offspring was also observed after respiratory infections or genital or reproductive tract infections. T. gondii infection in mothers was also described to be a risk factor. Interestingly, recent animal research showed that stressful events in later stages of life (during puberty, an especially vulnerable phase in life) unmask latent neuropathological consequences of prenatal immune activation [84]. This animal model might explain the delay between an early inflammation and the onset of schizophrenia years later.

Both infections before birth and infections, particularly of the CNS, during later stages of brain development increase the risk for later schizophrenia. Antibody titers against viruses have been examined in the sera of people with schizophrenia for many years, but the results have been inconsistent due to reasons such as interfering factors not being controlled for. Antibody levels are associated with the medication state, a finding which partly explains earlier controversial results. In one of our own studies, people with schizophrenia had higher titers of different pathogens than controls, a phenomenon that we call the ‘infectious index'.

Prenatal immune activation - regardless of whether it is triggered by infection - is an important risk factor for schizophrenia. In humans, increased maternal levels of the proinflammatory cytokine IL-8 during pregnancy were shown to increase the risk for schizophrenia in the offspring, whatever the reason for the increase in IL-8. Moreover, increased maternal IL-8 levels in pregnancy were also significantly related to decreased brain volume, leading to lower volumes of the right posterior cingulum and the left entorhinal cortex, and higher volumes of the ventricles in the offspring with schizophrenia (fig. 2).

Fig. 2

Pathoetiological model of psychiatric disorders with special emphasis on the influence of infections, inflammation and the immune system. Besides other environmental factors such as stress (chronic stress depletes the immune response), pathogens are an important factor. Immune genes are involved in psychiatric disorders. The activation or inhibition of the immune response influences the noradrenergic, serotonergic, dopaminergic and glutamatergic neurotransmission and the (neuroprotective and/or neurotoxic) tryptophan/kynurenine system, and through these mechanisms contributes to the psychopathology of psychiatric disorders. Anti-inflammatory drugs show beneficial effects in disorders such as schizophrenia or major depression.

Fig. 2

Pathoetiological model of psychiatric disorders with special emphasis on the influence of infections, inflammation and the immune system. Besides other environmental factors such as stress (chronic stress depletes the immune response), pathogens are an important factor. Immune genes are involved in psychiatric disorders. The activation or inhibition of the immune response influences the noradrenergic, serotonergic, dopaminergic and glutamatergic neurotransmission and the (neuroprotective and/or neurotoxic) tryptophan/kynurenine system, and through these mechanisms contributes to the psychopathology of psychiatric disorders. Anti-inflammatory drugs show beneficial effects in disorders such as schizophrenia or major depression.

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An immune-based therapeutic approach for psychiatric disorders was first proposed decades ago when the Nobel laureate Julius Wagner von Jauregg developed a vaccination therapy for psychoses [85]. He treated patients successfully with vaccines derived from attenuated Mycobacteriumtuberculosis, Plasmodium malariae or Salmonella Typhi, all of which stimulate a type 1 immune response [86]. This therapy showed the best results in syphilis infection, but Wagner von Jauregg also administered the vaccination therapy for other psychiatric disorders. After the introduction of penicillin and as a consequence of the overwhelming success of the neurotransmitter approach in psychiatry, the therapeutic vaccination approach was not pursued further. In the past decade, the emerging limitations of the neurotransmitter approach for pathogenetic research have resulted in increased interest in other therapeutic approaches, including the possible use of modern anti-inflammatory agents in schizophrenia [87]. The cyclooxygenase-2 (COX-2) inhibitor celecoxib was studied as an add-on to risperidone in a prospective, randomized, double-blind study of acute exacerbation of schizophrenia; patients receiving celecoxib had a statistically significant better outcome and showed an increase in the type 1 immune response [88]. The clinical effects of COX-2 inhibition in schizophrenia are especially pronounced in cognition [89]. The efficacy of therapy with a COX-2 inhibitor seems most pronounced in the first years of the schizophrenia disease process [90,91]. A recent study also found a beneficial effect of acetylsalicylic acid in schizophrenia spectrum disorders [92]. A recent meta-analysis on the use of nonsteroidal anti-inflammatory drugs in schizophrenia found a significant benefit of add-on treatment with nonsteroidal anti-inflammatory drugs on positive and negative symptoms and on the total symptomatology over all studies [93]. A second meta-analysis on the same topic, but based on a broader database, found a benefit only in the early stages of the disease, in particular in first manifestations of schizophrenia [94].

COX-2 inhibitors also showed interesting effects in animal models of depression. Treatment with the COX-2 inhibitor celecoxib, but not with a COX-1 inhibitor, prevented the dysregulation of the hypothalamic-pituitary-adrenal axis, in particular the increase of cortisol, one of the key biological features associated with depression [95,96]. This effect was expected because prostaglandin E2, which stimulates the hypothalamic-pituitary-adrenal axis in the CNS [97], is inhibited by COX-2 inhibition. The functional effects of IL-1 in the CNS, which include sickness behavior, were also shown to be antagonized by treatment with a selective COX-2 inhibitor [98].

COX-2 inhibitors also affect the CNS serotonergic system, either directly or via CNS immune mechanisms. In a rat model, treatment with rofecoxib was followed by an increase of serotonin in the frontal and temporoparietal cortex [99]. COX-2 inhibitors would be expected to show a clinical antidepressant effect since a lack of serotonin is one of the main factors in the pathophysiology of depression. The antidepressant action of COX-2 inhibitors may be mediated through inhibition of IL-1 and IL-6 release. In the depression model of bulbectomized rats, a decrease in hypothalamus cytokine levels and a change in behavior have been observed after chronic celecoxib treatment [100]. In another animal model of depression, however, the mixed COX-1/COX-2 inhibitor acetylsalicylic acid showed an additional antidepressant effect by accelerating the antidepressant effect of fluoxetine [101]. In an open-label pilot study in humans, acetylsalicylic acid also accelerated the antidepressant effect of fluoxetine and increased the response rate to monotherapy with fluoxetine in depressed nonresponders [102]. A significant therapeutic effect of the COX-2 inhibitor celecoxib in major depression was also found in a randomized, double-blind pilot add-on study [103]. Another randomized, double-blind study in 50 patients with major depression also showed a significantly better outcome with the COX-2 inhibitor celecoxib plus fluoxetine than with fluoxetine alone [104]. A similar result was obtained with a celecoxib add-on approach to sertraline in major depression [105,106]. A meta-analysis on the use of COX-2 inhibitors in major depression found an overall benefit of celecoxib add-on therapy [107].

Interestingly, etanercept, which blocks the interaction of TNF-α with the TNF-α cell surface receptors, showed a highly significant antidepressant effect [108]. A study with another TNF-α receptor blocker, infliximab, found no overall benefit in treatment-resistant patients with major depression, but did find a benefit in those with higher levels of inflammatory markers, such as CRP, TNF-α or soluble TNF receptors [106].

Although those preliminary data have to be interpreted cautiously and further research is needed to evaluate the therapeutic effects of COX-2 inhibitors in major depression, the results are encouraging for further studies on the inflammatory hypothesis of depression and the pathogenesis, course and therapy of the disease.

Maternal infection during pregnancy and childhood infections are risk factors for later schizophrenia, especially in combination with stress during puberty [84,109]. Furthermore, infections in later life are risk factors for both major depression [52] and schizophrenia [110]. In major depression, an inflammatory process seems to play a role in a subgroup of patients, but no specific infectious pathogens have been described. Stress and other environmental factors may contribute to the proinflammatory state. For example, animal models indicate that early life separation is associated with increased cytokine levels and passive behavior [111] and that early childhood stress disrupts the regulation of innate immune resistance to a challenge (lipopolysaccharide, viral infection), resulting in enhanced immunological and behavioral responses to immune activation in animals [112]. In people with depression, early-life stress is associated with enhanced inflammatory responsiveness to stress [113]. Moreover, a relationship between early childhood stress, inflammatory markers and depression in adult patients has been described [114,115]. Overall, studies indicate that stress and adverse events in childhood seem to be risk factors for an inflammatory state in adulthood.

There are further examples for the involvement of infections in psychiatric disorders. Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) manifests with tics, Tourette's syndrome and/or obsessive-compulsive symptoms [116], and is a consequence of streptococcal infection. However, not only Streptococcus but also other infectious agents such as Borrelia burgdorferi[117] or Mycoplasma pneumoniae [118,119] may directly or indirectly cause this syndrome. Therefore, the concept of pediatric infection-triggered autoimmune neuropsychiatric disorder, a postinfectious syndrome not restricted to streptococcal infection, was introduced [116,120]. The broader concepts of pediatric acute-onset neuropsychiatric syndrome [121] and childhood acute neuropsychiatric syndromes, which define a much broader clinical spectrum encompassing etiologically diverse entities, were recently proposed to overcome the criticism that the postinfectious syndrome might present with behavioral symptoms or comorbidities other than tics and obsessive-compulsive symptoms. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders have presented methodological limitations and are therefore inconclusive. Given the uncertainties regarding the clinical definition of PANDAS, it is not surprising that the evidence for a postinfectious, immune-mediated pathophysiology has to be further elucidated and specified [122]. However, therapeutic studies based on the PANDAS concept have shown that immunomodulating therapies, such as intravenous γ-immunoglobulin or plasmapheresis, have highly significant advantages compared to placebo [123].

The conceptual and terminological heterogeneity discussed above reflects the difficulties not only of postinfectious (auto-)immune syndromes, but also of infection- and immune-mediated disorders in psychiatry in general: the pathophysiological process is not fully elucidated, specific mechanisms still need to be explored and further scientific efforts are necessary. On the other hand, similar to the neurotransmitter-centered biological approach in psychiatry in which therapies were developed first and biological explanations came later, effective therapeutic approaches are on the way and may provide post hoc validation of the discussed concepts.

The possible influences of infection and immune processes on the pathogenesis of major psychiatric disorders resulting in inflammation have long been neglected. Increasing evidence for a role of proinflammatory cytokines in major depression and schizophrenia, the strong influence of pro- and anti-inflammatory cytokines on the tryptophan/kynurenine metabolism and - related to that mechanism - the influence of cytokines on the glutamatergic neurotransmission support the view that infection, psychoneuroimmunology and inflammation rightly should be a focus of psychiatric research. This view is fostered by the results of (immuno-) genetic findings and the exhibited therapeutic effects of anti-inflammatory drugs in schizophrenia and major depression. On the other hand, it is possible that immunological research in patients may be susceptible to artefacts; interfering variables such as medication, smoking, stress, sleep and others play an important role and cannot always been controlled. This can be shown by the example of stress: stress is not only - according to the ‘vulnerability-stress-model' of schizophrenia - a condition sine qua non in schizophrenia, it is also a confounding factor for research of the immune system and inflammatory processes.

These considerations show that further research is needed to clarify the role of infection and of the immune system in psychiatric disorders. Recent results encourage placing further emphasis on this fascinating field. Therapeutic studies, including meta-analyses, support the view that therapeutic progress based on anti-inflammatory and/or immunomodulating approaches are not only of theoretical interest, but may have an important clinical impact and might lead to a paradigm change in psychiatric therapy.

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